Influence of Exceptional Patient Characteristics on Everolimus Exposure (INPRES)

A study to determine whether everolimus pharmacokinetics in elderly and obese patients is different compared to control patients.

Furthermore the investigators will investigate the relation between metabolic response assessed with [18F] Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) and everolimus exposure and clinical benefit.

The investigators will explore whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: everolimus dose escalation

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Boxmeer, Netherlands
    • Maasziekenhuis Pantein
  • Hoofddorp, Netherlands
    • Spaarne Gasthuis
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Nieuwegein, Netherlands
    • St. Antonius Ziekenhuis
  • Nijmegen, Netherlands
    • Radboud university medical center
  • Uden, Netherlands
    • Bernhoven Ziekenhuis
  • Zwolle, Netherlands
    • Isala Klinieken

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
• Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
• Postmenopausal women
• Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment.
• Progression following a non-steroidal aromatase inhibitor

• Falling into one of the following categories

  • elderly patients (age ≥ 70 years and BMI < 30 kg/m2); or
  • obese patients (BMI ≥ 30 kg/m2 and age < 70 years); or
  • control patients (BMI < 30 kg/m2 and age < 70 years);
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
• Adequate renal function: calculated creatinine clearance, as estimated by GFR using the MDRD formula, is ≥ 30ml/min/1.73m2
• Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)
• Patient is willing and able to sign the Informed Consent Form prior to screening evaluations

Exclusion Criteria:

• Patients aged ≥ 70 years AND BMI ≥ 30 kg/m2
• HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
• Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting.
• Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
• Patients with a known history of HIV seropositivity.

• Any severe and / or uncontrolled medical conditions such as:

  • Unstable angina pectoris, serious uncontrolled cardiac arrhythmia
  • Patients with severe hepatic impairment (Child-Pugh A/B/C)
  • Uncontrolled diabetes mellitus
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
• Patients who test positive for hepatitis B or C
• Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment
• History of non-compliance to medical regimens
• Patients unwilling to or unable to comply with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: standard care; everolimus dose is continued independently of everolimus AUC
Active Comparator: everolimus dose escalation; patients with an AUC below mean will have dose escalation of everolimus based on their AUC	Drug: everolimus dose escalation; patients with an AUC below mean will have dose escalation of everolimus based on their AUC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
everolimus AUC	The primary aim is to show a difference in everolimus exposure (AUC0-24hr) of at least 25% in elderly patients (≥70 years) and obese patients (BMI ≥ 30 kg/m2) compared to the control group (≤ 70 years; BMI ≤ 30 kg/m2), after reaching steady state everolimus pharmacokinetics (day 14, but at least after 7 days of everolimus therapy).	day 14 after start treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
correlation between early metabolic response and PFS	To explore and calculate the predictive value of early metabolic response assessment with clinical benefit (PFS defined as disease progression according to RECIST version 1.1 or death, whichever occurs first) as primary outcome measure. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan.	within 90 days after start of treatment
correlation between early metabolic response and AUC	To quantify the correlation between early metabolic response and everolimus exposure (AUC0-24hr) on steady-state pharmacokinetics. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan.	15 days after start of treatment
effect dose escalation on metabolic respons	To explore, quantify and describe whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan.	within 36 days after start of treatment
correlation between AUC and frequency of adverse event	To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0.	4 months after start of treatment

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Novartis
• Investigators: Principal Investigator: Carla van Herpen, MD, PhD, Radboud university medical center, department of medical oncology; Principal Investigator: Nielka van Erp, PharmD, PhD, Radboud university medical center, department of Pharmacy

Publications and helpful links

General Publications

• Willemsen AECAB, de Geus-Oei LF, de Boer M, Tol J, Kamm Y, de Jong PC, Jonker MA, Vos AH, Grootjans W, de Groot JWB, Mulder SF, Aarntzen EHJG, Gerritsen WR, van Herpen CML, van Erp NP. Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane. Target Oncol. 2018 Oct;13(5):641-648. doi: 10.1007/s11523-018-0596-8.

Helpful Links

• Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): January 15, 2018
• Study Completion (Actual): January 15, 2018

Study Registration Dates

• First Submitted: September 13, 2013
• First Submitted That Met QC Criteria: September 19, 2013
• First Posted (Estimate): September 24, 2013

Study Record Updates

• Last Update Posted (Actual): December 7, 2018
• Last Update Submitted That Met QC Criteria: December 5, 2018
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: pharmacokinetics; everolimus; Breast Neoplasms; elderly patients; obese patients
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: UMCNONCO201301